ArticleJournal of advanced research2026
Spike RBD drives sustained Parkinson's disease progression via microglia-neuron crosstalk-mediated RTP801 upregulation.
Article in Journal of advanced research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.Journal of neuroinflammation · 2026Review
- Dual immune modulation of microglia in viral encephalitis: current understanding and future perspectives.Frontiers in molecular biosciences · 2025Review
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionEmerging evidence highlights the exacerbation and sustained Parkinson's disease (PD) progression following COVID-19. The SARS-CoV-2 spike receptor-binding domain (RBD), which can persist in the brain post-infection, is a likely contributor, but how it drives this neuropathology is unclear.
objectivesTo elucidate the underlying mechanisms of long COVID's impact on PD and identify mechanism that contribute to the continuous progression of PD.
methodsThe SARS-CoV-2 spike RBD was stereotactically injected into the substantia nigra pars compacta of α-synuclein (αSyn) A53T mice within a chronic stress-genetic susceptibility model. We characterized the pathological impact of RBD using motor and non-motor behavioral tests, fMRI-based functional connectivity, in vivo electrophysiology, immunofluorescence, and αSyn aggregate analysis. To elucidate the underlying mechanisms, we then employed RNA-sequencing, transmission electron microscopy, microglial depletion, and comparative studies in αSyn A53T mice lacking RTP801 (αSyn A53T
resultsRBD accelerated PD-related motor and non-motor symptom deterioration, impaired brain functional connectivity, and reduced neuronal excitability. It exacerbated dopaminergic neuron degeneration and αSyn aggregation. RTP801 was identified as a critical mediator of RBD-induced PD progression, with its sustained upregulation in dopaminergic neurons dependent on microglial activation. Mechanistically, initially activates microglia induced an increase in neuronal RTP801 via IL-6 and IL-8. RBD leaded to mitochondrial dysfunction, mtDNA release, and activation of the cGAS-STING pathway between neurons and microglia, triggering a mtDNA-cGAS-STING-IFNβ/RTP801 feedback loop, driving neurodegeneration.
conclusionsOur findings demonstrate that SARS-CoV-2 RBD exacerbates PD progression through a pathogenic crosstalk between microglia and neurons. This neurotoxic signaling is mediated by a mitochondrial mtDNA-cGAS-STING-IFNβ/RTP801 axis. Targeting RTP801 or the STING pathway may therefore represent a promising therapeutic strategy to mitigate long COVID-associated progression of PD.
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